Cancers arise and progress by a series of genetic and biochemical events that remain to be fully described. During the initial period of support for this project, we have characterized several mouse models of breast carcinoma by examining morphological features, lymph node dependence, their genotypes and expression phenotypes, and mechanisms of oncogenesis by Wnt signaling elements. We have also learned to deliver viral vectors to mammary and pancreatic islet cells and have confirmed the ability of two candidate genes to promote tumor progression in islet cells. In the new proposal, we continue to use a variety of mouse models of breast cancer and a model of islet cell carcinogenesis, plus three dimensional tissue culture methods and materials from stored human tumor samples, to explore several issues related to the molecular basis of neoplasia. Virus vectors will be used to assess many genes and micro-RNAs as contributors to tumor progression in the pancreatic and mammary cancer models. We will seek to understand the phenomenon of oncogene dependence by using conditional oncogenic transgenes and viral vectors to identify factors that protect tumors from oncogene-dependence. And we will explore our preliminary evidence that oncogenesis by components of Wnt signaling pathways is mediated by fibroblast growth factors or members of the protein kinase C (PKC) family.